Over the past decade many successes in identifying mutations responsible for human illness have been for relatively uncommon diseases which are inherited in simple mendelian patterns. More recent years have seen attention turn to attempts to elucidate genetic alterations associated with common diseases such as cancer, diabetes and a variety of neurodegenerative disorders. Several lines of evidence suggest that such mutations might be present at high frequencies, have low penetrance and involve distinct genes in different individuals with similar phenotypes. Further, it is likely, that epistatic interactions between multiple genetic and environmental factors will be required before disease develops. As a practical matter, it is often easiest to identify these types of mutations in genetically homogeneous populations. Once such group are Ashkenazi Jews of eastern and middle European origin. Although there is no evidence that they have an overall greater burden of genetic illness than other groups, common mutations most likely due to founder effect and genetic drift have been detected at a comparatively high frequency. A recent study examining the penetrance of common founder mutations in BRCA1 and BRCA2, two genes associated with inherited forms of breast cancer, resulted in the collection of DNA samples and family histories of cancer from a sample of approximately 5000 Ashkenazi Jews from the Baltimore-Washington area. These valuable resources provide powerful tools for the characterization of common DNA sequence variations potentially associated with the development of cancer. Mutations in four genes with common, potentially disease-associated alleles will be investigated for increased cancer risk in the above-mentioned cohort of Ashkenazim. A multiplex PCR assay is being developed that will allow simultaneous amplification of DNA products from portions of APC, the gene mutated in familial adenomatosis (6% carrier frequency), BLM, which is mutated in Bloom syndrome (1% carrier frequency), FACC, which is mutated in Fanconi anemia, complementation group C (1% carrier frequency) and MTHFR, methylene tetrahydrofolate reductase, an enzyme involved in intracellular folate metabolism (approximately 40% carrier frequency). The relative risk of cancer (in particular colon cancer in the cases of APC and MTHFR) among relatives of carriers and non-carriers will allow estimation of penetrance of each mutation. Furthermore, this dataset will be able to be examined for epistatic interactions in individuals who are carriers of multiple mutations.